Is PHKA2 p.Trp43Ser (c.128G>C) pathogenic?

PHKA2 p.Trp43Ser (c.128G>C) is classified Likely pathogenic in PHKA2 (ClinVar, Single submitter, 1 submitter; last evaluated 2017-11-15). AlphaMissense: likely pathogenic (0.9742); Absent from gnomAD v4.1; Associated with glycogen storage disease IXa1.

What condition is associated with PHKA2 p.Trp43Ser (c.128G>C)?

PHKA2 p.Trp43Ser (c.128G>C) is associated with glycogen storage disease IXa1 (ClinVar).

How common is PHKA2 p.Trp43Ser (c.128G>C) in the general population?

PHKA2 p.Trp43Ser (c.128G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about PHKA2 p.Trp43Ser (c.128G>C)?

AlphaMissense predicts likely pathogenic (score 0.9742) — an in-silico prediction, not a clinical call.

PHKA2 p.Trp43Ser

Q: How is Glycogen storage disease due to liver phosphorylase kinase deficiency inherited?

Typically Autosomal recessive, X-linked recessive (Orphanet). A genetic counselor can assess individual risk for a family.

c.128G>C · rs1556016365 · VCV488576

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9742 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

glycogen storage disease IXa1

Computational evidence

Protein change
AlphaMissense	0.9742	likely pathogenic ✓ concordant with ClinVar · top 10% in PHKA2
REVEL	0.903	moderately pathogenic-leaning
SaProt	LLR -13.18	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.5	GERP 2.2, phastCons 1
Regional constraint	o/e 0.67	unconstrained · MANE · 45 kb · p 5e-08 · regional, not allelic
Overall
CADD	28.5	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: PHKA2
Protein: p.Trp43Ser
Coding: c.128G>C
MANE Select: NM_000292
dbSNP: rs1556016365
Type: single nucleotide variant
Location: chrX:18954363 (GRCh38)
Structure: AlphaFold pLDDT 81.36

Full PHKA2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

glycogen storage disease IXa1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Glycogen storage disease due to liver phosphorylase kinase deficiency (Orphanet):

Inheritance: Autosomal recessive, X-linked recessive
Onset: Childhood
Prevalence: 1-9 / 100 000 (Europe)

Similar variants

PHKA2 c.1325-2A>G Likely pathogenic ★★ same condition
PHKA2 c.2597+1G>A Pathogenic/Likely pathogenic ★★ same condition
PHKA2 c.537+2T>C Pathogenic/Likely pathogenic ★★ same condition
PHKA2 c.918+1G>A Pathogenic/Likely pathogenic ★★ same condition
PHKA2 p.Arg1111Ter Pathogenic ★★ same condition
PHKA2 p.Arg186Cys Pathogenic/Likely pathogenic ★★ same condition
PHKA2 p.Arg186His Likely pathogenic ★★ same condition
PHKA2 p.Arg295Cys Pathogenic/Likely pathogenic ★★ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/phka2-p-trp43ser (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown